title: EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk.
abstract: In an effort to identify novel biallelically inactivated tumor suppressor genes (TSGs) in sporadic invasive and preinvasive non-small-cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multiple 'omics' approach to investigate patient-matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes and in the earliest stages of lung cancer. We found that decreased EYA4 expression is not only associated with poor survival in sporadic lung cancers but also that EYA4 single-nucleotide polymorphisms are associated with increased familial cancer risk, consistent with EYA4s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we found that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross-examination of EYA4 expression across multiple tumor types suggests a cell-type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC.
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: I M
authors.initials: IM
authors.lastname: Wilson
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: E A
authors.initials: EA
authors.lastname: Vucic
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: K S S
authors.initials: KS
authors.lastname: Enfield
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Y A
authors.initials: YA
authors.lastname: Zhang
authors.affiliation: 1] Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chari
authors.affiliation: 1] Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada [2] National Human Genome Research Institute, Cancer Genetics Branch, Bethesda, MD, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Radulovich
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Starczynowski
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Banáth
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Pusic
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Fuller
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Lonergan
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Rowbotham
authors.affiliation: Department of Surgery, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Yee
authors.affiliation: Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: English
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: T P H
authors.initials: TP
authors.lastname: Buys
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Selamat
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.affiliation: Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.affiliation: Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: You
authors.affiliation: Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: M S
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Department of Medical Genetics, University of British Columbia, Life Sciences Centre, Vancouver, BC, Canada.
authors.forename: C J
authors.identifier: 0000000289590101
authors.initials: CJ
authors.lastname: Brown
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Bennewith
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: C E
authors.initials: CE
authors.lastname: MacAulay
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Karsan
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lam
authors.affiliation: Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: W L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology* / Q000235:genetics; D002896:Chromosomes, Human, Pair 6; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C117736:EYA4 protein, human; D015534:Trans-Activators